Pharmaceutical preparation in the form of a supension comprising an acid-labile active ingredient

ABSTRACT

The present invention relates to the field of pharmaceutical technology and describes a novel pharmaceutical preparation in the form of a suspension comprising an acid-labile active ingredient, in particular an acid-labile proton pump inhibitor. The invention also relates to processes for producing the suspension. The suspension is particularly suitable for administering acid-labile active ingredients to people who have difficulty taking solid dosage forms such as tablets or capsules.

TECHNICAL FIELD

[0001] The present invention relates to the field of pharmaceuticaltechnology and describes a novel pharmaceutical preparation in the formof a suspension comprising an acid-labile active ingredient, inparticular an acid-labile proton pump inhibitor. The invention alsorelates to processes for producing the suspension. The suspension isparticularly suitable for administering acid-labile active ingredientsto people who have difficulty taking solid dosage forms such as tabletsor capsules.

BACKGROUND ART

[0002] It is generally known to coat oral dosage forms, e.g. tablets orpellets, which comprise an acid-labile active ingredient, with anenteric coating which, after passing through the stomach, rapidlydissolves in the alkaline medium in the intestine. One example of suchacid-labile active ingredients comprises acid-labile proton pumpinhibitors (H⁺/K⁺-ATPase inhibitors), in particularpyridin-2-ylmethylsulfinyl-1H-benzimidazoles like those disclosed, forexample, in EP-A-0 005 129, EP-A-0 166 287, EP-A-0 174 726 and EP-A-0268 956. Because of their H⁺/K⁺-ATPase-inhibiting effect, they areimportant in the therapy of disorders originating from increased gastricacid secretion. Examples of active ingredients from this group which arealready commercially available are5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: omeprazole),5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: pantoprazole),2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: lansoprazole) and2-([4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl}-1H-benzimidazole(INN: rabeprazole).

[0003] Because of their great tendency to decompose in a neutral and, inparticular, acidic environment, with production also of highly coloreddecomposition products, it is also necessary in this case for oralpreparations to protect active ingredients from the effect of acids.With the very acid-labile pyridin-2-ylmethylsulfinyl-1H-benzimidazolesit is additionally necessary for them to be processed in the tablet coreor in pellets in the form of their alkaline salts, for example as sodiumsalts, or together with alkaline substances. Since substances suitablefor enteric coatings are those with free carboxyl groups, the problemarises that the enteric coating is, because of the alkaline medium inthe interior, partially or even completely dissolved from inside, andthe free carboxyl groups promote decomposition of the active ingredient.It is therefore necessary to provide a sealing intermediate layer(subcoating) between the enteric coating and the alkaline tablet core orpellet. EP-A-0 244 380 proposes that cores which contain the activeingredient together with alkaline compounds or as alkaline salt becoated with at least one layer which is soluble in water or rapidlydisintegrates in water and is composed of nonacidic, inertpharmaceutically acceptable substances, before the enteric layer isapplied. The intermediate layer or intermediate layers act aspH-buffering zones in which hydrogen ions diffusing in from outside areable to react with the hydroxyl ions diffusing out of the alkaline core.In order to increase the buffer capacity of the intermediate layer, itis proposed to incorporate buffer substances into the intermediatelayer(s). By this process it is possible in practice to obtainreasonably stable preparations. However, relatively thick intermediatelayers are required in order to avoid the unsightly discolorations whichoccur even with only slight decomposition. In addition, considerableeffort must be invested to avoid traces of moisture during production.

[0004] The administration of solid dosage forms such as capsules ortablets proves to be problematic especially in animals or patients whohave difficulties with swallowing, such as, for example, elderly peopleand small children.

[0005] WO94/25070 describes an oral pharmaceutical preparationcomprising a proton pump inhibitor in the form of a paste for treatingacid-related gastric disorders in animals. For this purpose, entericcoated particles (such as tablets or beads) which comprise a proton pumpinhibitor either are mixed with dry gelling agents, and this mixture isthen mixed with water immediately before administration, or the entericparticles are mixed with potassium or calcium salts and mixedimmediately before administration with a low-viscosity solution of apolymeric gel-forming agent. An alternative proposal is to mix entericcoated particles immediately before administration with a low-viscositysolution of a gel-forming agent in the form of a temperature-sensitivepolymer, and to heat the solution cautiously. The preparations describedherein have the disadvantage for the user, however, that the paste mustbe prepared immediately before administration.

[0006] U.S. Pat. No. 5,708,017 and WO00/50038 describe an oralpharmaceutical preparation which is ready for use and comprisesomeprazole in the form of a paste for treating acid-related gastricdisorders in humans and animals. This preparation in paste formcomprises omeprazole, basifying agents, a thickener and a hydrophobic,oily liquid vehicle. The hydrophobic oily liquid vehicle comprises avegetable oil and triglycerides of medium chain length fatty acids orpropylene glycol diesters of medium chain length fatty acids. Accordingto WO00/50038, these preparations are stable and can be used to fillsyringes which can then be used directly for administering the activeingredient to an animal.

DESCRIPTION OF THE INVENTION

[0007] It is an object of the present invention to provide a juice(hereinafter also referred to as suspension) for the oral administrationof acid-labile active ingredients which can be produced without greattechnical complexity, which is stable and not sensitive to moisture anddisplays good controllability of active ingredient delivery. It oughtalso to be possible to produce the suspension ready for use. Anotherobject of the invention is also to provide a suspension for the oraladministration of acid-labile active ingredients, where it isunnecessary to protect the acid-labile active ingredient by an entericcoating.

[0008] It has now been found, surprisingly, that this object can beachieved by a pharmaceutical preparation where a plurality of individualactive ingredient units are dispersed in a thickened base composed ofone or more pharmaceutical excipients, where the acid-labile activeingredient is present in the individual active ingredient units in amatrix composed of a mixture comprising at least one solid paraffin andone or more substances from the group of fatty alcohol, triglyceride andfatty acid ester.

[0009] The invention therefore relates to a pharmaceutical preparationin juice (suspension) form for oral administration of an acid-labileactive ingredient where a plurality of individual active ingredientunits are dispersed in a thickened base composed of one or morepharmaceutical excipients, where the acid-labile active ingredient ispresent in the individual active ingredient units in a matrix composedof a mixture comprising at least one solid paraffin and one or moresubstances from the group of fatty alcohol, triglyceride and fatty acidester.

[0010] The invention therefore further relates to a pharmaceuticalpreparation in suspension form for oral administration of an acid-labileactive ingredient where a plurality of individual active ingredientunits are dispersed in a thickened base composed of one or morepharmaceutical excipients, where the acid-labile active ingredient ispresent in the individual active ingredient units i) in a matrixcomposed of a mixture comprising at least one fatty alcohol and at leastone solid paraffin, ii) in a matrix composed of a mixture comprising atleast one triglyceride and at least one solid paraffin or iii) in amatrix composed of a mixture comprising at least one fatty acid esterand at least one solid paraffin.

[0011] The dosage form can according to the invention be in the form ofa powder for reconstitution, that is to say the ingredients are in theform of a dry mixture. The powder for reconstitution is mixed with waterimmediately before use and must then be consumed within a specifiedperiod. The dosage form of the invention is preferably a suspensionready for use.

[0012] The pharmaceutical preparation of the invention can be producedwithout great technical complexity. Technically complicated processesfor applying enteric layers and intermediate layers are unnecessary. Inaddition, the controllability of active ingredient deliveries from thesuspension is observed to be good. Surprisingly, this suspension readyfor use is also observed to have good chemical and physical stability.

[0013] Further subject matters are evident from the claims.

[0014] The numerous individual active ingredient units (also referred tohereinafter as preparations) for the purposes of the invention comprisenumerous individual units in which at least one active ingredientparticle, preferably a plurality of active ingredient particles, ispresent in a matrix composed of a mixture comprising at least one solidparaffin and one or more substances from the group of fatty alcohol,triglyceride and fatty acid ester. A plurality of active ingredientparticles is preferably present i) in a matrix composed of a mixturecomprising at least one fatty alcohol and at least one solid paraffin,ii) in a matrix composed of a mixture of at least one triglyceride andat least one solid paraffin or iii) in a matrix composed of a mixture ofat least one fatty acid ester and at least one solid paraffin. Theactive ingredient is preferably present in essentially uniformdistribution, in particular homogeneously dispersed or dissolved, in thematrix. The active ingredient units are preferably microspheres.

[0015] The active ingredient units of the invention are distinguished inparticular by high stability, an active ingredient release which can becontrolled via the particle size and composition of the matrix, goodflow characteristics, good processibility and a uniform delivery ofactive ingredient. It is particularly worthy of mention that the activeingredient units of the invention can be further processed to thesuspension without thereby losing a given functionality (such as tastemasking, resistance to gastric juice, slowing of release) in thesuspension base.

[0016] The particle size of the individual units is advantageously lessthan or equal to 2 mm, preferably 50-800 μm, particularly preferably50-700 μm and very particularly preferably 50-600 μm. Microspheres witha particle size of 50-500 μm, particularly preferably of 50-400 μm, arepreferred. Mono-modal microspheres with a particle size of 50-400 μm,particularly preferably of 50-200 μm, are particularly preferred.

[0017] Examples of acid-labile active ingredients in the sense of thepresent invention are acid-labile proton pump inhibitors.

[0018] Acid-labile proton pump inhibitors (H⁺/K⁺-APTase inhibitors) inthe sense of the present invention which should be particularlymentioned are substituted pyridin-2-ylmethylsulfinyl-1H-benzimidazoleslike those disclosed, for example, in EP-A-0 005 129, EP-A-0 166 287,EP-A-0 174 726, EP-A-0 184 322, EP-A-0 261 478 and EP-A-0 268 956. Thosewhich may be mentioned as preferred in this connection are5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl)-1H-benzimidazole(INN: omeprazole),5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole(INN: pantoprazole),2-[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl)methylsulfinyl)-1H-benzimidazole(INN: lansoprazole) and2-{[4-(3-methoxypropoxy)-3-methylpyridin-2-yl]methylsulfinyl)-1H-benzimidazole(INN: rabeprazole).

[0019] Further acid-labil proton pump inhibitors, for examplesubstituted phenylmethylsulfinyl-1H-benzimidazoles,cycloheptapyridin-9-ylsulfinyl-1H-benzimidazoles orpyridin-2-ylmethylsulfinylthienoimidazoles are disclosed in DE-A 35 31487, EP-A-0 434 999 and EP-A-0 234 485. Examples which may be mentionedar 2-[2-(N-isobutyl-N-methylamino)benzylsulfinyl]benzimidazole (INN:leminoprazole) and2-(4-methoxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ylsulfinyl)-1H-benzimidazol(INN: nepaprazole).

[0020] The acid-labile proton pump inhibitors are chiral compounds. Theterm “acid-labile proton pump inhibitor” also encompasses the pureenantiomers of the acid-labile proton pump inhibitors and their mixturesin any mixing ratio. Pure enantiomers which may be mentioned by way ofexample are5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole(INN: esomeprazole) and (S)-pantoprazole[(−)-pantoprazole].

[0021] The acid-labile proton pump inhibitors are moreover present assuch or, preferably, in the form of their salts with bases. Examples ofsalts with bases which may be mentioned are sodium, potassium, magnesiumor calcium salts. If the acid-labile proton pump inhibitors are isolatedin crystalline form, they may contain variable amounts of solvent. Theterm acid-labile proton pump inhibitor therefore also representsaccording to the invention all soivates, in particular all hydrates, ofthe acid-labile proton pump inhibitors and their salts. Such a hydrateof the salt of an acid-labile proton pump inhibitor with a base isdisclosed, for example, in WO91/19710.

[0022] Acid-labile proton pump inhibitors which may be mentioned asparticularly preferred are pantoprazole sodium sesquihydrate(=pantoprazole sodium×1.5 H₂O), (−)-pantoprazole sodium sesquihydrate,Pantoprazole magnesium dihydrate, omeprazole magnesium, omeprazole andesomeprazole.

[0023] The fatty alcohol is preferably a linear, saturated orunsaturated primary alcohol with 10-30 carbon atoms. It is preferably aprimary alcohol with 10 to 18 carbon atoms in linear chains. Examples offatty alcohols which may be mentioned are cetyl alcohol, myristylalcohol, lauryl alcohol or stearyl alcohol, with preference for cetylalcohol. It is also possible if desired for mixtures of fatty alcoholsto be present.

[0024] The triglyceride is glycerol with its three hydroxyl groupsesterified by carboxylic acids. The carboxylic acids are preferablymonobasic carboxylic acids with 8 to 22 carbon atoms, preferablynaturally occurring carboxylic acids. It is possible in this case forthe carboxylic acids to be different or, preferably, identical. Exampleswhich may be mentioned are tristearate, tripalmitate and, particularlypreferably, trimyristate (these triglycerides are commercially availableunder the name Dynasan 118, 116 and 114 respectively). It is alsopossible if desired for mixtures of triglycerides to be present.

[0025] The fatty acid ester is the ester of an alcohol with a fattyacid. The alcohol in this case is preferably a linear, saturated orunsaturated primary alcohol with 10-30, preferably with 12 to 18, carbonatoms. The fatty acid is preferably a monobasic carboxylic acid with 8to 22, in particular 12 to 18, carbon atoms, preferably a naturallyoccurring carboxylic acid. Fatty acid esters preferred according to theinvention have a melting point above 30° C. Examples of fatty acidesters which may be mentioned are cetyl palmitate, which is commerciallyavailable for example under the name Cutina® CP. It is also possible ifdesired for mixtures of fatty acid esters to be present.

[0026] The solid paraffin is preferably paraffinum solidum (ceresin). Itis also possible alternatively to use ozokerite, for example. It is alsopossible if desired to use mixtures.

[0027] If desired, the mixtures in the individual active ingredientunits may include one or more other pharmaceutically suitableexcipients. Other suitable excipients which may be mentioned by way ofexample are polymers, sterols and basic compounds.

[0028] Examples of polymers which may be mentioned are povidone (e.g.Kollidon® 17, 30 and 90 from BASF), vinylpyrrolidone/vinyl acetatecopolymer and polyvinyl acetate. Others which may be mentioned arecellulose ethers [such as, for example, methylcellulose, ethylcellulose(Ethocel®) and hydroxypropylmethylcellulose], cellulose esters [such ascellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT),hydroxypropylmethylcellulose phthalate (HP50 and HP55) orhydroxypropylmethylcellulose acetate succinate (HPMCAS)], methacrylicacid/methyl methacrylate copolymer or methacrylic acid/ethylmethacrylate copolymer (Eudragit® L). The polymer is preferably povidoneor ethylcellulose. It is also possible if desired for mixtures ofpolymers to be present. It is possible by adding suitable polymers, forexample, to influence the pharmaceutical properties of the individualactive ingredient units (e.g. delivery of the active ingredient).

[0029] The sterol is preferably a phytosterol or a zoosterol. Examplesof phytosterols which may be mentioned are ergosterol, stigmasterol,sitosterol, brassicasterol and campesterol. Examples of zoosterols whichmay be mentioned are cholesterol and lanosterol. It is also possible ifdesired for mixtures of sterols to be present.

[0030] Examples of suitable basic compounds are inorganic basic saltssuch as ammonium carbonate and sodium carbonate, salts of fatty acidssuch as sodium stearate, amines such as meglumine, di-, triethylamineand TRIS(2-amino-2-hydroxymethyl-1,3-propanediol) or fatty-amines suchas stearylamine. Stearylamine and sodium stearate may be mentioned aspreferred. The addition of basic compounds to the mixtures in theindividual units results in particularly stable preparations andprevents possible discolorations.

[0031] The proportion (in percent by weight) of active ingredient in theindividual active ingredient unit is advantageously 1-90%. Theproportion of active ingredient is preferably 2-70%, particularlypreferably 5-40%, in particular 10-20%. The proportion of fatty alcoholin the individual active ingredient unit is advantageously 10-70%,preferably 20-70%, particularly preferably 20-60% and in particular30-60%.

[0032] The proportion of triglyceride in the individual activeingredient unit is advantageously 10-70%, preferably 20-70%,particularly preferably 20-60% and in particular 30-60%. The proportionof fatty acid ester in the individual active ingredient unit isadvantageously 10-70%, preferably 20-70%, particularly preferably 20-60%and in particular 30-60%. The proportion of solid paraffin isadvantageously 10-70%, preferably 20-60% and in particular 30-60%. Ifpresent, the proportion of polymer in the individual active ingredientunit is expediently 1-25%, preferably 1-10%, particularly preferably5-10%. If present, the proportion of sterol is expediently 1-10%,preferably 1-5%. If present, the proportion of basic compound is0.05-5%, preferably 0.1-1%.

[0033] Preferred individual active ingredient units of the inventionconsist of 2-70% active ingredient, 10-60% fatty alcohol, 10-60% solidparaffin, 1-15% polymer and 0.1-2% of a basic compound. Furtherpreferred individual active ingredient units of the invention consist of2-70% active ingredient, 10-60% triglyceride, 10-60% solid paraffin,1-15% polymer and 0.1-2% of a basic compound. Other preferred individualactive ingredient units of the invention consist of 2-70% activeingredient, 10-60% fatty acid ester, 10-60% solid paraffin, 1-15%polymer and 0.1-2% of a basic compound.

[0034] Particularly preferred individual active ingredient units of theinvention consist of 5-40% active ingredient, 20-60% fatty alcohol,10-60% solid paraffin, 1-15% polymer and 0.1-1% of a basic compound.Further particularly preferred individual active ingredient units of theinvention consist of 5-40% active ingredient, 20-60% triglyceride,10-60% solid paraffin, 1-15% polymer and 0.1-1% of a basic compound.Other particularly preferred individual active ingredient units of theinvention consist of 5-40% active ingredient, 20-60% fatty acid ester,10-60% solid paraffin, 1-15% polymer and 0.1-1% of a basic compound.

[0035] Examples of active ingredient units of the invention contain5-40% pantoprazole sodium sesquihydrate, 10-40% cetyl alcohol, 5-60%solid paraffin, 1-5% polymer and 0.1-0.2% of a basic compound. Furtherexamples of active ingredient units of the invention contain 5-40%pantoprazole sodium sesquihydrate, 10-40% glyceryl tripalmitate, 5-60%solid paraffin, 1-5% polymer and 0.1-0.2% of a basic compound. Otherexamples of active ingredient units of the invention contain 5-40%pantoprazole sodium sesquihydrate, 10-40% glyceryl tripalmitate, 5-60%solid paraffin, 1-5% polymer and 0.1-0.2% of a basic compound. Stillother examples of active ingredient units of the invention contain10-20% pantoprazole sodium sesquihydrate, 20-40% triglyceride, 40-70%solid paraffin, 1-5% sterol and 0.05-0.1% of a basic compound.

[0036] The individual active ingredient units can be produced forexample by spray drying or, preferably, by spray solidification, inparticular also by spray prilling. Production is particularly preferablyby prilling, in particular by vibration prilling.

[0037] For the spray solidification or prilling expediently the fattyalcohol, the triglyceride or the fatty acid ester is liquefied togetherwith the solid paraffin and, if desired, other excipients to give aclear melt. The active ingredient is dissolved or dispersed in thissolution, and the resulting solution or dispersion is sprayed or,preferably, prilled in a suitable apparatus. A dispersion of the activeingredient in a melt of the excipients is preferably used.

[0038] Spray solidification takes place in a manner known per se. Adetailed description of this technique is to be found in P. B. Deasy,Microencapsulation and Related Drug Processes (1984).

[0039] The individual active ingredient units are particularlypreferably produced by solidification from liquid phase by generatingdrops by means of vibrating nozzles and by solidifying the drops whichare formed, after they have stabilized, by drying or cooling in asuitable medium (preferably gaseous or liquid). The suitable medium maybe, for example, cooled gas such as air or nitrogen. Processes of thistype and corresponding apparatuses are disclosed in DE 27 25 924, EP 0467 221, WO99/33555 and WO00124382. It is particularly preferred in thisconnection for the liquid phase flowing to the nozzle to be kept at aconstant temperature. The solidification preferably takes place byinstantaneous cooling in a suitable cooling medium. In prilling,moreover it is preferred for the liquid phase flowing to the nozzle, thevibrating nozzle and the drops formed by prilling to be kept at aconstant temperature until their spherical shape has stabilized, and forthe solidification of the drops after their stabilization to be carriedout instantaneously by cooling with a gaseous or liquid cooling medium.Systems suitable for prilling by means of vibrating nozzles aremarketed, for example, by Brace GmbH, Alzenau, Germany. It is possibleby means of prilling using vibrating nozzles to obtain the individualactive ingredient units in the form of microspheres with a narrowmonomodal particle size spectrum in the particle size range from 50 μmto 2 mm. The narrow monomodal particle size spectrum and the uniformspherical shape of the microspheres obtained in this way are expected toresult in a uniformly smooth surface, a uniform, defined delivery ofactive ingredient and, in relation to passage through the stomach in thecase of oral dosage forms (owing to the small particles), a behaviorlike that of a solution. The microspheres of the invention aredistinguished in particular by high stability, a release of activeingredient which can be controlled via the particle size and compositionof the matrix, good flow characteristics, good processibility and auniform delivery of active ingredient. It is particularly worthy ofmention that the microspheres can be-further processed-to the-suspensionwithout thereby losing a given functionality (such as taste masking,resistance to gastric juice, slowing of release) in the thickened base.

[0040] The microspheres are preferably monomodal microspheres with aparticle size range of 50-800 μm, preferably 50-500 μm, particularlypreferably 50-400 μm, in particular 50-200 μm. The microspherespreferably comprise an acid-labile proton pump inhibitor.

[0041] The particle size of the active ingredient employed in the spraydrying or spray solidification, prilling or vibration prilling isadvantageously less than or equal to 100 μm, in particular less than 40μm. The particle size is preferably in the range 1-20 μm, particularlypreferably in the range 3-15 μm. Such a particle size can be achieved,for example, by grinding the active ingredient in a suitable mill.

[0042] The individual active ingredient units (preparations) of theinvention can then be further processed together with suitableexcipients to give the suspension of the invention—in the form of apowder for reconstitution or ready for use. Suitable exciplents are, inparticular, those excipients normally used to produce suspensions.Excipients particularly suitable according to the invention are thosewith which a thickened base can be produced, such as thickeners.Examples of thickeners according to the invention are xanthan,substituted celluloses, polyvinylpyrrolidone (polyvidone types), sheetsilicates, alginates or alginic acids. A mixture of two or moredifferent thickeners is also possible if desired. The proportion ofthickener depends on the desired viscosity or consistency which thesuspension ready for use is to have. A particularly preferred suspensionhas a viscosity of less than 500 mPa.s (determined with a rotationalviscometer). The proportion of xanthan based on the suspension ready foruse is usually from 0.1 to 1% by weight. The proportion of substitutedcelluloses depends on the viscosity levels of the celluloses and isnormally from 0.1 to 10% by weight based on the suspension ready foruse. Examples of substituted celluloses of the invention which may bementioned are carboxymethylcellulose, ethylcellulose, methylcellulose orhydroxypropylcellulose. The proportion of polyvinylpyrrolidone(polyvidone types) is normally from 0.1 to 10% by weight based on thesolution ready for use. Sheet silicates such as Veegum or bentonites canbe employed alone or in combination with water-soluble thickeners. Thetotal proportion of thickener is then advantageously from 0.1 to 7% byweight based on the suspension ready for use. Alginates and alginic acidare normally employed in a proportion of from 0.1 to 10% by weight basedon the suspension ready for use. Other pharmaceutical excipientspreferably employed are insoluble crosslinked polyvinylpyrrolidone(crospovidone) and microcrystalline cellulose. It is observed in thiscase that a loose sediment forms and prevents agglomeration ofindividual active ingredient units. The ratio of crospovidone to theindividual active ingredient units is advantageously from 1:1 to 0.5:1(based on weight). Microcrystalline cellulose, which is normallyemployed in a proportion of from 0.5 to 5% by weight based on thesuspension ready for use, is likewise suitable for this purpose. Theproportion of individual active ingredient units in the suspension readyfor use is usually according to the invention from 1 to 20% by weightbased on the suspension ready for use, preferably from 1 to 15% byweight and very preferably from 5 to 10% by weight. Water is preferablyused as solvent or dispersant for the suspension

[0043] Other suitable excipients which may be present in the suspensionof the invention are, for example, flavoring substances (such asflavorings and sweeteners), buffer substances, preservatives or elseemulsifiers. Flavors are usually added in a proportion of from 0.05 to1% by weight. Other examples of flavoring substances are acids such ascitric acid, sweeteners such as saccharin, aspartame, cyclamate sodiumor maltol, which are added according to the desired result. Examples ofemulsifiers are lecithins, sodium lauryl sulfate, Tweens® or Spans,which are normally added in a proportion of from 0.01 to 1% by weight.Preservatives such as benzoic acid, salts of benzoic acid, methyl4-hydroxybenzoate, propyl 4-hydroxybenzoate, sorbic acid or saltsthereof are preferably also added. The proportion depends on thepreservative used and is usually from 0.1 to 4% by weight based on thesuspension ready for use.

[0044] The suspension of the invention is produced by techniques knownto the skilled worker. If a powder for reconstitution is to be produced,there is preferably production of a mixture of the individual activeingredient units with the thickener and, where appropriate, otherexcipients. This mixed powder for reconstitution is then mixed with asuitable amount of water immediately before administration. Suspensionready for use is normally produced by introducing the individual activeingredient units into a dispersion of the thickener and, whereappropriate, of additives in water or, alternatively, by introducing thethickener into a dispersion of the individual active ingredient units inwater.

[0045] The pharmaceutical preparations of the invention in suspensionform are administered in amounts which contain the acid-labile activeingredient in the dose usual for treating the particular disorder. Theacid-labile proton pump inhibitors of the invention can be used for thetreatment and prevention of all disorders regarded as treatable orpreventible by use of pyridin-2-ylmethylsulfinyl-1H-benzimidazoles. Inparticular, the suspension of the invention can be employed in thetreatment of gastric disorders. As mentioned above, the suspension ofthe invention is particularly suitable for oral administration of theactive ingredient to humans who have difficulties with swallowing solidoral forms, such as elderly people or else children. For administrationto humans, the suspension of the invention is provided in amounts whichcontain between 1 and 500 mg, preferably between 5 and 60 mg, of anacid-labile proton pump inhibitor. Examples which may be mentioned areunits of the suspensions of the invention which contain 10, 20, 40 or 50mg of pantoprazole. Administration of the daily dose (for example 40 mgof active ingredient) can take place for example in the form of a singledose or by means of several doses of the suspension of the invention(for example 2×20 mg of active ingredient). The total volume ofsuspension for an administration unit is advantageously from 1 to 10 ml.The suspension of the invention is preferably provided in a special packwhich may also at the same time assist administration. Examples whichmay be mentioned are bags or bottles. Compared with solid oral forms,the suspension of the invention has the advantage for the patient thatit can be taken very simply and anywhere because, in the case of thesuspension ready for use, intake is possible even without water, forexample directly from a bag or bottle. The suspension additionallypermits individual dosage.

[0046] The suspension of the invention can be combined with othermedicaments, either in different combinations or in a fixed combination.Combinations worthy of mention in connection with the dosage forms ofthe invention which comprise acid-labile proton pump inhibitors asactive ingredients are those with anti-microbial active ingredients andcombinations with NSAIDs (nonsteroidal anti-inflammatory drugs).Particular mention should be made of the combination with antimicrobialagents like those employed for controlling the microbe Helicobacterpylori (H. pylori).

[0047] Examples of suitable antimicrobial active ingredients (activeagainst Helicobacter pylori) are described in EP-A-0 282 131. Examplesof antimicrobial agents which are suitable for controlling the microbeHelicobacter pylori and may be mentioned by way of example are bismuthsalts [e.g. bismuth subcitrate, bismuth subsalicylate, ammoniumbismuth(III) potassium citrate dihydroxide, bismuth nitrate oxide,dibismuth tris(tetraoxodialuminate)], but especially β-lactamantibiotics, for example penicillins (such as benzylpenicillin,phenoxymethylpenicillin, propicillin, azidocillin, dicloxacillin,flucloxacillin, oxacillin, amoxicillin, bacampicillin, ampicillin,meziocillin, piperacillin or azlocillin), cephalosporins (such ascefadroxil, cefaclor, cefalexin, cefixime, cefuroxime, cefetamet,ceftibuten, cefpodoxime, cefotetan, cefazoline, cefoperazone,ceftizoxime, cefotaxime, ceftazidime, cefamandole, cefepime, cefoxitin,cefodizime, cefsulodin, ceftriaxone, cefotiam or cefmenoxime) or otherβ-lactam antibiotics (e.g. aztreonam, loracarbef or meropenem); enzymeinhibitors, for example sulbactam; tetracyclines, for exampletetracycline, oxytetracycline, minocycline or doxycycline;aminoglycosides, for example tobramycin, gentamicin, neomycin,streptomycin, amikacin, netilmicin, paromomycin or spectinomycin;amphenicols, for example chloramphenicol or thiamphenicol; lincomycinsand macrolide antibiotics, for example clindamycin, lincomycin,erythromycin, clarithromycin, spiramycin, roxithromycin or azithromycin;polypeptide antibiotics, for example colistin, polymixin B, telcoplaninor vancomycin; gyrase inhibitors, for example norfiloxacin, cinoxacin,ciprofloxacin, pipemidic acid, enoxacin, nalidixic acid, pefloxacin,fieroxacin or ofloxacin; nitrolmidazoles, for example metronidazole; orother antibiotics, for example fosfomycin or fusidic acid. Particularlyworthy of mention in this connection is the administration of anacid-labile proton pump inhibitor together with the combination of aplurality of antimicrobial active ingredients, for example with thecombination of a bismuth salt and/or tetracycline with metronidazole orthe combination of amoxicillin or clarithromycin with metronidazole andamoxicillin with clarithromycin.

[0048] The production of dosage forms and preparations of the inventionis described by way of example hereinafter. The following examplesexplain the invention in detail without restricting it.

EXAMPLES

[0049] Production of the Active Ingredient Units

Example 1

[0050] 50 g of solid paraffin, 34.9 g of cetyl alcohol and 0.1 g ofstearylamine are converted into a clear melt. 5.0 g of povidone isdissolved in the clear melt. At a temperature between 56-60° C., 10.0 gof pantoprazole sodium sesquihydrate is added and suspendedhomogeneously. The suspension is prilled in the molten state, and thedrops thus produced are solidified in a cooling zone.

Example 2

[0051] 55 g of solid paraffin, 30.9 g of cetyl alcohol and 0.1 g ofstearylamine are converted into a clear melt. 4.0 g of povidone isdissolved in the clear melt. At a temperature between 56-60° C., 10.0 gof pantoprazole magnesium is added and suspended homogeneously. Thesuspension is prilled in the molten state, and the drops thus producedare solidified in a cooling zone.

Example 3

[0052] 45.0 g of solid paraffin, 33.8 g of cetyl alcohol, 1.0 g ofβ-sitosterol and 0.2 g of stearylamine are converted into a clear melt.1.0 g of povidone and 4.0 g of ethylcellulose are dissolved in the clearmelt. At a temperature between 56-60° C., 15.0 g of pantoprazole sodiumsesquihydrate is added and suspended homogeneously. The suspension isprilled in the molten state, and the drops thus produced are solidifiedin a cooling zone.

Example 4

[0053] 52.0 g of solid paraffin, 30.3 g of cetyl alcohol and 0.2 g ofstearylamine are converted into a clear melt. 5.0 g of povidone isdissolved in the clear melt. At a temperature between 56-60° C., 12.5 gof pantoprazole sodium sesquihydrate is added and suspendedhomogeneously. The suspension is prilled in the molten state, and thedrops thus produced are solidified in a cooling zone.

Example 5

[0054] 77.2 g of cetyl alcohol and 0.3 g of stearylamine are convertedinto a clear melt. 10.0 g of povidone is dissolved in the clear melt. Ata temperature between 56-60° C., 12.5 g of pantoprazole sodiumsesquihydrate is added and suspended homogeneously. The suspension isprilled in the molten state, and the drops thus produc d are solidifiedin a cooling zone.

Example 6

[0055] 47 g of solid paraffin, 40 g of glyceryl tripalmitate (Dynasan116, from Hüls) and 3 g of sitosterol are converted into a clear melt at100° C. and cooled to 55-60° C. 10 g of lansoprazole are added andsuspended homogeneously. The suspension is put in the feed container ofa prilling unit (from Brace) and prilled from a 200 μm nozzle at about0.1 bar. A periodic vibration with a frequency of about 390 Hz istransmitted to the nozzle head during this. The resulting drops aresolidified in a cooling zone with air at a temperature of −30° C.

Example 7

[0056] 15 g of glyceryl trimyristate (Dynasan 114), 15 grams of glyceryltripalmitate (Dynasan 116), 50 grams of solid paraffin and 5 g ofcholesterol are converted into a clear melt at about 100° C. The clearmelt is cooled to about 55-65° C. 15 g of rabeprazole are added, theactive ingredient is uniformly dispersed, and the homogeneous suspensionis prilled as in example 6.

Example 8

[0057] 10 g of glyceryl tripalmitate (Dynasan 116), 20 g of glyceryltrimyristate (Dynasan 114), 52 g of solid paraffin and 3 g of sitosterolare converted into a clear melt at about 100° C. The clear melt iscooled to 55-65° C. 15 g of omeprazole Mg are added and suspendedhomogeneously. The suspension is put in the feed container of a prillingunit (from Brace) and prilled through a 200 μm nozzle at 90 mbar. Aperiodic vibration with a frequency of about 400 Hz is transmitted tothe nozzle head during this. The resulting drops are solidified with airat a temperature of −30° C. in a cooling zone.

Example 9

[0058] 18 g of tristearin, 60 g of solid paraffin and 5 g of cholesterolare converted into a clear melt. The clear melt is cooled to 56-60° C.10 g of pantoprazole sodium sesquihydrate are introduced andhomogeneously dispersed. The suspension is prilled in the molten statein a prilling unit (from Brace) with vibrating nozzles, and theresulting drops are solidified in a cooling zone.

Example 10

[0059] 18 g of cetyl palmitate, 40 g of solid paraffin and 2 g ofcholesterol are converted into a clear melt. The clear melt is cooled to56-60° C. 10 g of pantoprazole sodium sesquihydrate are introduced andhomogenized until a uniform suspension results. The suspension isprilled in the molten state in a prilling unit (from Brace) withvibrating nozzles, and the resulting drops are solidified in a coolingzone.

Example 11

[0060] 50 g of solid paraffin and 40 g of cetyl palmitate (Cutina® CP)are converted into a clear melt at 100° C. The clear melt is cooled to50-60° C. 10 g of pantoprazole sodium sesquihydrate are introduced andsuspended homogeneously. The suspension is prilled in the molten statein a prilling unit (from Brace) with vibrating nozzles (200 μm nozzle),and the resulting drops are solidified in a cooling zone.

Example 12

[0061] 50 g of solid paraffin and 40 g of cetyl alcohol are convertedinto a clear melt at 100° C. The clear melt is cooled to 50-60° C. 10 gof pantoprazole sodium sesquihydrate are introduced and suspendedhomogeneously. The suspension is prilled in the molten state in aprilling unit (from Brace) with vibrating nozzles (200 μm nozzle), andthe resulting drops are solidified in a cooling zone.

Example 13

[0062] 50 g of solid paraffin and 40 g of glyceryl trimyristate areconverted into a clear melt at 100° C. The clear melt is cooled to50-60° C. 10 g of pantoprazole sodium sesquihydrate are introduced andsuspended homogeneously. The suspension is prilled in the molten statein a prilling unit (from Brace) with vibrating nozzles (200 μm nozzle),and the resulting drops are solidified in a cooling zone.

Example 14

[0063] 47 g of solid paraffin, 40 g of glyceryl tripalmitate (Dynasan116, from Hüls) and 3 g of sitosterol are converted into a clear melt at100° C. and cooled to 50-60° C. 10 g of lansoprazole are added andsuspended homogeneously. The suspension is put into the feed containerof a prilling unit (from Brace) and prilled from a 200 μm nozzle atabout 0.1 bar. A periodic vibration with a frequency of about 390 Hz istransmitted to the nozzle head during this. The resulting drops aresolidified in a cooling zone with air at a temperature of −30° C.

Example 15

[0064] 30 g of tristearin, 60 g of solid paraffin and 4 g of sitosteroland 0.07 g stearylamine are converted into a clear melt. The clear meltis cooled to 56-60° C. 15 g of pantoprazole sodium sesquihydrate areintroduced and homogeneously dispersed. The suspension is prilled in themolten state in a prilling unit (from Brace) with vibrating nozzles, andthe resulting drops are solidified in a cooling zone.

Example 16

[0065] 17.59 of glyceryl trimyristate (Dynasan 114), 67.5 g of solidparaffin and 5 g of cholesterol are converted into a clear melt at about100° C. The clear melt is cooled to about 55-65° C. 10 g of pantoprazoleare added, and the active ingredient is uniformly dispersed, and thehomogeneous suspension is prilled as in example 6.

Example 17

[0066] 56.7 g of cetyl alcohol, 3 g of vinylpyrollidone/vinyl acetatecopolymer, 15 g of solid paraffin, 15 g of cetyl palmitate and 0.1 g ofsodium stearate are converted into a clear melt. At a temperaturebetween 56-60° C., 10.0 g of pantoprazole sodium sesquihydrate is addedand suspended homogeneously. The suspension is prilled in the moltenstate at 60° C. and the drops thus produced are solidified in a coolingzone.

Example 18

[0067] 46.7 g of cetostearylic alcohol, 4 g of vinylpyrollidone/vinylacetate copolymer, 23 g solid paraffin, 0.3 g of sodium stearate and 1 gsitosterol are converted into a clear melt. At a temperature between60-65° C., 10.0 g of pantoprazole sodium sesquihydrate is added andsuspended homogeneously. The suspension is prilled in the molten stateat 60 to 65° C. and the drops thus produced are solidified in a coolingzone.

Example 19

[0068] 39.9 g of cetyl alcohol, 3 g of vinylpyrollidone/vinyl acetatecopolymer, 20 g of cetyl palmitate, 2 g cholesterol, 17 g solid paraffinand 0.1 g of sodium stearate are converted into a clear melt. At atemperature between 56-60° C., 18.0 g of pantoprazole sodiumsesquihydrate is added and suspended homogeneously. The suspension isprilled in the molten state at 60° C. and the drops thus produced aresolidified in a cooling zone.

Example 20

[0069] 47.9 g cetostearylic alcohol, 2 g of vinylpyrollidone/vinylacetate copolymer, 25 g of cetyl palmitate, 1 g sitosterol, 15 g solidparaffin and 0.1 g of sodium stearate are converted into a clear melt.At a temperature between 56-60° C., 15.0 g of pantoprazole sodiumsesquihydrate is added and suspended homogeneously. The suspension isprilled in the molten state at 60° C. and the drops thus produced aresolidified in a cooling zone.

[0070] The preparations obtained as in examples 1-20 have a particlesize in the range 50-700 μm. It is possible, for example by varying theprocess conditions, to obtain larger particles.

[0071] Production of Solutions of the Invention

Example A

[0072] 0.1 g of cyclamate sodium and 0.1 g of sodium benzoate aresuccessively added to and dissolved in 100 ml of purified water. 4.0 gof a preparation obtained as in Example 1 are then stirred into thesolution obtained in this way. 0.2 g of xanthan is added, and themixture is stirred until uniform swelling is achieved. Flavors are alsoadded if desired.

Example B

[0073] 0.1 g of cyclamate sodium and 0.15 g of sodium benzoate aresuccessively added to and dissolved in 100 ml of purified water. 4.0 gof a preparation obtained as in Example 8 are then stirred into thesolution obtained in this way. 0.2 g of xanthan and 0.5 g ofhydroxypropylmethylcellulose 15 cps are added, and the mixture isstirred until uniform swelling is achieved. Flavors are also added ifdesired.

Example C

[0074] 0.1 g of cyclamate sodium and 0.15 g of sodium benzoate aresuccessively added to and dissolved in 100 ml of purified water. 3.0 gof crospovidone are then dispersed with a stirrer in the solutionobtained in this way. 6.0 g of a preparation obtained as in Example 6are stirred into the dispersion. 1.5 g of hydroxypropylmethylcellulose15 cps are added, and the mixture is stirred until uniform swelling isreached. Flavors are also added if desired.

Example D

[0075] 0.1 g of cyclamate sodium and 0.2 g of sorbic acid aresuccessively added to and dissolved in 100 ml of purified water. 3.0 gof crospovidone are then dispersed with a stirrer in the solutionobtained in this way. 4.0 g of a preparation obtained as in Example 2are stirred into the dispersion. 2.0 g of hydroxypropylmethylcellulose15 cps are added, and the mixture is stirred until uniform swelling isreached. Flavors are also added if desired.

Exampl E

[0076] 0.1 g of cyclamate sodium and 0.15 g of sorbic acid aresuccessively added to and dissolved in 100 ml of purified water. 2.0 gof microcrystalline cellulose are then dispersed with a stirrer in thesolution obtained in this way. 8.0 g of a preparation obtained as inExample 9 are stirred into the dispersion. 2.0 g of Polyvidone 30 areadded, and the mixture is stirred until uniform swelling is reached.Flavors are also added if desired.

1. A pharmaceutical preparation in juice (suspension) form for oraladministration of an acid-labile active ingredient where a plurality ofindividual active ingredient units are dispersed in a thickened basecomposed of one or more pharmaceutical excipients, where the acid-labileactive ingredient is present in the individual active ingredient unitsin a matrix composed of a mixture comprising at least one solid paraffinand one or more substances from the group of fatty alcohol, triglycerideand fatty acid ester.
 2. A pharmaceutical preparation in juice(suspension) form for oral administration of an acid-labile activeingredient where a plurality of individual active ingredient units aredispersed in a thickened base composed of one or more pharmaceuticalexcipients, where the acid-labile active ingredient is present in theindividual active ingredient units i) in a matrix composed of a mixturecomprising at least one fatty alcohol and at least one solid paraffin,ii) in a matrix composed of a mixture comprising at least onetriglyceride and at least one solid paraffin or iii) in a matrixcomposed of a mixture comprising at least one fatty acid ester and atleast one solid paraffin.
 3. A pharmaceutical preparation as claimed inclaim 1, which is a suspension ready for use.
 4. A pharmaceuticalpreparation as claimed in claim 1, where the base is aqueous, and atleast one thickener selected from the group of xanthan, substitutedcelluloses, polyvinylpyrrolidone [polyvidone types], sheet silicates,algihates or alginic acids is present as excipient.
 5. A pharmaceuticalpreparation as claimed in claim 1, where a mixture of two or moredifferent thickeners is present.
 6. A pharmaceutical preparation asclaimed in claim 1, where the proportion of thickener based on thepreparation ready for use is from 0.1 to 10% by weight.
 7. Apharmaceutical preparation as claimed in claim 4, where an excipientselected from the group of flavors, flavoring substances, buffersubstances, preservatives or emulsifiers is additionally present.
 8. Apharmaceutical preparation as claimed in claim 1, wherein an acid-labileproton pump inhibitor is present as active ingredient.
 9. Apharmaceutical preparation as claimed in claim 8, wherein pantoprazole,a salt of pantoprazole, a solvate of pantoprazole or a salt thereof ispresent as acid-labile proton pump inhibitor.
 10. A dosage form for oraladministration of an acid-labile active ingredient, comprising apreparation as claimed in claim 1, where the preparation is pres nt in acontainer suitable for oral administration.